This project is concerned with the identification and characterization of the receptor for FMRFamide (Phe-Met-Arg-Phe-NH2), a widely distributed neuropeptide. FMRFamine receptors were solubilized from squid brain using the zwitterionic detergent CHAPS. The solubilized receptor bound FMRFamide with Kd about 0.15 Nm and displayed a structure-activity relationship similar to that of the receptor in unsolubilized squid membranes. Ligand affinity was sensitive to guanine nucleotides, indicating the coupling of the receptor to a G protein- regulated pathway and consistent with earlier work demonstrating the stimulation of squid adenylate cyclase by FMRFamide. Current efforts are directed towards obtaining an estimate of the molecular size of the receptor. An earlier approach using photoreactive analogues of FMRFaminde identified a protein of 52 kDa, but subsequent work suggested that this protein is not the receptor on the basis of differences in ligand specificity and affinity, and GTP sensitivity. This protein may be an enzyme involved in peptide processing because of its specificity for FMRFamide in comparison to the non-amidated FMRF.